Rociletinib is an oral irreversible-mutation third-generation epidermal growth factor receptor (EGFR) inhibitor developed by Clovis Oncology. The drug can inhibit key activating mutation and T790M resistance mutation, leaving a wild-type EGFR signal inactive. On May 20, 2014, the FDA awarded Breakthrough Therapy Designation to this experimental drug, for the second-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC) carrying T790M as a single-drug therapy. Since the drug does not have a standard Chinese translation, the applicant transliterated this as “luoxitini” by transliterating.
The chemical name of rociletinib (I) is: N-[3-[[2-[[4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)-4-pyrimidyl]amino]phenyl]-2-acrylamide, and the structural formula is:

International patents WO2012061299, WO2013138502 and WO2014182593 reported on the synthesis of rociletinib. The core preparation steps include condensation reactions of a parent nucleus A and a side chain B. As for the sequence of Boc-protection and acryloylation reaction on the parent nucleus A and the order of N-protection and acetylation reaction on piperazine on the side chain B, corresponding changes can be made according to different reaction requirements, and have no significant impact on the overall reaction route.

The synthesis steps of the parent nucleus A and the side chain B are as follows:
As for the parent nucleus A, 2,4-dichloro-5-trifluoromethylpyrimidine serving as a raw material is subjected to a 4-chlorine substitution reaction with N-Boc-m-phenylenediamine to generate a parent nucleus intermediate A, the intermediate A can be directly subjected to a condensation reaction with the side chain B to generate a protected intermediate C, and the intermediate C is subjected to deprotection and acryloylation reaction to obtain the target compound rociletinib. The parent nucleus A can also be directly subjected to deprotection and acryloylation reaction to obtain another parent nucleus intermediate A′, and the intermediate A′ reacts with the side chain B to directly produce rociletinib.

The side chain B is prepared by performing a halogenation reaction and a nitro reduction reaction on a raw material N-acetylpiperazidine.

By analyzing the above synthetic route, although the target compound rociletinib can be successfully prepared for the first time, there are still disadvantages such as unobtainable raw materials, too many steps, low yield of partial reactions and the like. Especially for the parent nucleus A, on the one hand, raw materials are difficult to obtain, and more importantly, the activities of two chlorine atoms on the pyrimidine ring are not much different, so that the selectivity of two substitution reactions of aromatic amines is poor, thereby having an adverse effect on the overall yield of the preparation and on the purification of the aftertreatment.
In view of the existing process defects, a preparation technology which is simple in process, economical, environment-friendly and superior in quality has been developed. In particular, the search for a process that can adapt to industrial production has important practical significance for improving the economic and social benefits of the drug.